Positive association between chlorinated paraffins and the risk of allergic diseases in children and adolescents.

Contaminants may induce immune response polarization, leading to immune diseases, such as allergic diseases. Evidence concerning the effects of chlorinated paraffins (CPs), an emerging persistent organic pollutant, on immune system is scarce, particularly for epidemiological evidence. This study explores the association between CPs exposure and allergic diseases (allergic rhinitis, atopic eczema, and allergic conjunctivitis) in children and adolescents in the Pearl River Delta (PRD) in China. Herein, 131,304 children and adolescents from primary and secondary schools in the PRD were included and completed the questionnaire survey. The particulate matter (PM) samples were collected in the PRD and the PM2.5-bound CP concentrations were analyzed. In the multivarious adjustment mixed effect model (MEM), an IQR increase in ∑CPs was significantly associated with allergic diseases (rhinitis, eczema, and conjunctivitis) with the estimated odds ratios (ORs) for 1.11 (95% CI: 1.10, 1.13), 1.17 (95% CI: 1.15, 1.19), and 1.82 (95% CI: 1.76, 1.88), respectively. Interaction analysis indicated that overweight and obese individuals might have greater risk. Similar effect estimates were observed in several sensitivity analyses. This study provided epidemiological evidence on the immunotoxicity of CPs. More studies to confirm our findings and investigate mechanisms are needed.

Plasma proteomic characterization of colorectal cancer patients with FOLFOX chemotherapy by integrated proteomics technology.

BACKGROUND: Colorectal Cancer (CRC) is a prevalent form of cancer, and the effectiveness of the main postoperative chemotherapy treatment, FOLFOX, varies among patients. In this study, we aimed to identify potential biomarkers for predicting the prognosis of CRC patients treated with FOLFOX through plasma proteomic characterization. METHODS: Using a fully integrated sample preparation technology SISPROT-based proteomics workflow, we achieved deep proteome coverage and trained a machine learning model from a discovery cohort of 90 CRC patients to differentiate FOLFOX-sensitive and FOLFOX-resistant patients. The model was then validated by targeted proteomics on an independent test cohort of 26 patients. RESULTS: We achieved deep proteome coverage of 831 protein groups in total and 536 protein groups in average for non-depleted plasma from CRC patients by using a Orbitrap Exploris 240 with moderate sensitivity. Our results revealed distinct molecular changes in FOLFOX-sensitive and FOLFOX-resistant patients. We confidently identified known prognostic biomarkers for colorectal cancer, such as S100A4, LGALS1, and FABP5. The classifier based on the biomarker panel demonstrated a promised AUC value of 0.908 with 93% accuracy. Additionally, we established a protein panel to predict FOLFOX effectiveness, and several proteins within the panel were validated using targeted proteomic methods. CONCLUSIONS: Our study sheds light on the pathways affected in CRC patients treated with FOLFOX chemotherapy and identifies potential biomarkers that could be valuable for prognosis prediction. Our findings showed the potential of mass spectrometry-based proteomics and machine learning as an unbiased and systematic approach for discovering biomarkers in CRC.

Moniezia benedeni infection increases IgE+ cells in sheep (Ovis aries) small intestine.

The concentration of immunoglobulin (Ig) E is the lowest among serum Igs, but it can induces type I hypersensitivity and plays an important role in anti-parasitic infection. The present study aimed to explore the residence characteristics of IgE+ cells in the sheep small intestine and the impact of Moniezia benedeni infection on them. The recombinant plasmids pET-28a-IgE were constructed and induced and expressed in Escherichia coli. BL21 (DE3). The rabbit anti-sheep IgE polyclonal antibody was prepared using the obtained recombinant protein as antigen. Finally, the levels of IgE+ cells in the small intestine of healthy (Control group) and naturally M. benedeni-infected (Infected group) sheep were detected analyzed. The results showed that the rabbit anti-sheep IgE polyclonal antibody with good immunogenicity (titer = 1: 128000) could specifically bind to the heavy chain of natural sheep IgE. In the Control group, the IgE+ cells were mainly distributed in lamina propria of the small intestine, and the densities were significantly decreased from duodenum to ileum (P<0.05), with respective values of (4.28 cells / 104 µm2, 1.80 cells / 104 µm2, and 1.44 cells / 104 µm2 in duodenum, jejunum, and ileum. In the Infected group, IgE+ cells density were 6.26 cells / 104 µm2, 3.01 cells / 104 µm2, and 2.09 cells / 104 µm2 in duodenum, jejunum and ileum respectively, which were significantly higher in all segments compared to the Control group (P<0.05), increasing by 46.26%, 67.22% and 45.14%, respectively. In addition, compared with the Control group, the IgE protein levels were significantly increased in all intestinal segments of the Infected group (P<0.01), however, there was no significant differences among the different intestinal segments within the same group (P>0.05). The results demonstrated that M. benedeni infection could significantly increase the content of IgE and the distribution density of its secreting cells in sheep small intestine. The intestinal mucosal immune system of sheep presented obvious specificity against M. benedeni infection. This lays a good foundation for further exploring molecular mechanisms of the intestinal mucosal immune system monitoring and responding to M. benedeni infection.

Pain Comorbidities with Attention Deficit: A Narrative Review of Clinical and Preclinical Research.

A negative correlation exists between attention and pain. The cognitive impairments linked to pain can significantly impede a patient's healing process and everyday tasks, particularly for individuals experiencing persistent pain. Furthermore, it has been demonstrated that diversion can effectively decrease pain levels in individuals. The focus of this review is to analyze clinical trials and fundamental investigations regarding alterations in focus and persistent discomfort. Moreover, we investigated the common neuroanatomy associated with attention and pain. Furthermore, we examined the impact of various neuromodulators on the transmission of pain and processes related to attention, while also considering the potential neural mechanisms that contribute to the co-occurrence of pain and attention deficits. Further investigation in this field will enhance our comprehension of patient symptoms and the underlying pathophysiology, ultimately resulting in more objective approaches to treatment.

Prediction of pathologic complete response to neoadjuvant chemoradiation in locally advanced rectal cancer.

Purpose: To investigate the predictive factors of pathologic complete response (pCR) in locally advanced rectal cancer (LARC) patients who had been treated with neoadjuvant chemoradiation (nCRT). Methods and materials: For this retrospective study, 53 LARC patients (37 males and 16 females; age range 25 to 79 years) were selected. Clinical characteristics, baseline mrTNM staging, MR gross tumor volumes (GTV), and pCR were evaluated. The diagnostic accuracy of GTV for predicting pCR was calculated. Results: Among 53 LARC patients, 15 patients achieved pCR (28.3%), while 38 patients achieved non-pCR. Only three (5.7%) out of 53 patients did not downstage after nCRT. GTV and tumor differentiation were the significant prognostic parameters for predicting pCR. A tumor volume threshold of 21.1 cm3 was determined as a predictor for pCR, with a sensitivity of 84% and specificity of 47%. In addition, GTV was associated with mrN stage, circumferential resection margin (CRM) status, extramural vascular invasion (EMVI) status, and pretreatment serum CEA level. Conclusion: Tumor volume and tumor differentiation have significant predictive values in preoperative assessment of pCR among LARC patients. These findings aid clinicians to discriminate those patients who may likely benefit from preoperative regimens and to make optimal treatment plans.

The effects of flow settings during high-flow nasal cannula oxygen therapy for neonates and young children.

BACKGROUND: During neonatal and paediatric high-flow nasal cannula therapy, optimising the flow setting is crucial for favourable physiological and clinical outcomes. However, considerable variability exists in clinical practice regarding initial flows and subsequent adjustments for these patients. Our review aimed to summarise the impact of various flows during high-flow nasal cannula treatment in neonates and children. METHODS: Two investigators independently searched PubMed, Embase, Web of Science, Scopus and Cochrane for in vitro and in vivo studies published in English before 30 April 2023. Studies enrolling adults (≥18 years) or those using a single flow setting were excluded. Data extraction and risk of bias assessments were performed independently by two investigators. The study protocol was prospectively registered with PROSPERO (CRD42022345419). RESULTS: 38 406 studies were identified, with 44 included. In vitro studies explored flow settings' effects on airway pressures, humidity and carbon dioxide clearance; all were flow-dependent. Observational clinical studies consistently reported that higher flows led to increased pharyngeal pressure and potentially increased intrathoracic airway pressure (especially among neonates), improved oxygenation, and reduced respiratory rate and work of breathing up to a certain threshold. Three randomised controlled trials found no significant differences in treatment failure among different flow settings. Flow impacts exhibited significant heterogeneity among different patients. CONCLUSION: Individualising flow settings in neonates and young children requires consideration of the patient's peak inspiratory flow, respiratory rate, heart rate, tolerance, work of breathing and lung aeration for optimal care.

LDLR is used as a cell entry receptor by multiple alphaviruses.

Alphaviruses are arboviruses transmitted by mosquitoes and are pathogenic to humans and livestock, causing a substantial public health burden. So far, several receptors have been identified for alphavirus entry; however, they cannot explain the broad host range and tissue tropism of certain alphaviruses, such as Getah virus (GETV), indicating the existence of additional receptors. Here we identify the evolutionarily conserved low-density lipoprotein receptor (LDLR) as a new cell entry factor for GETV, Semliki Forest virus (SFV), Ross River virus (RRV) and Bebaru virus (BEBV). Ectopic expression of LDLR facilitates cellular binding and internalization of GETV, which is mediated by the interaction between the E2-E1 spike of GETV and the ligand-binding domain (LBD) of LDLR. Antibodies against LBD block GETV infection in cultured cells. In addition, the GST-LBD fusion protein inhibits GETV infection both in vitro and in vivo. Notably, we identify the key amino acids in LDLR-LBD that played a crucial role in viral entry; specific mutations in the CR4 and CR5 domain of LDLR-LBD reduce viral entry to cells by more than 20-fold. These findings suggest that targeting the LDLR-LBD could be a potential strategy for the development of antivirals against multiple alphaviruses.

Risk assessment of SARS-CoV-2 replicating and evolving in animals.

The retransmissions of SARS-CoV-2 from several mammals - primarily mink and white-tailed deer - to humans have raised concerns for the emergence of a new animal-derived SARS-CoV-2 variant to worsen the pandemic. Here, we discuss animal species that are susceptible to natural or experimental infection with SARS-CoV-2 and can transmit the virus to mates or humans. We describe cutting-edge techniques to assess the impact of a mutation in the viral spike (S) protein on its receptor and on antibody binding. Our review of spike sequences of animal-derived viruses identified nine unique amino acid exchanges in the receptor-binding domain (RBD) that are not present in any variant of concern (VOC). These mutations are present in SARS-CoV-2 found in companion animals such as dogs and cats, and they exhibit a higher frequency in SARS-CoV-2 found in mink and white-tailed deer, suggesting that sustained transmissions may contribute to maintaining novel mutations. Four of these exchanges, such as Leu452Met, could undermine acquired immune protection in humans while maintaining high affinity for the human angiotensin-converting enzyme 2 (ACE2) receptor. Finally, we discuss important avenues of future research into animal-derived viruses with public health risks.

AHA Life's Essential 8 and new-onset CKD: a prospective cohort study from the UK Biobank.

BACKGROUND: The AHA has recently introduced a novel metric, Life's Essential 8, to assess cardiovascular health (CVH). Nevertheless, the association between varying levels of LE8 and the propensity for CKD is still unclear from a large prospective cohort. Our objective is to meticulously examine the relationship between LE8 and its associated susceptibilities to CKD. METHODS: A total of 251,825 participants free of CKD from the UK Biobank were included. Cardiovascular health was scored using LE8 and categorized as low, moderate, and high. Cox proportional hazard models were employed to evaluate the associations of LE8 scores with new-onset CKD. The genetic risk score for CKD was calculated by a weighted method. RESULTS: Over a median follow-up of 12.8 years, we meticulously documented 10,124 incident cases of CKD. Remarkably, an increased LE8 score correlated with a significant reduction of risk in new-onset CKD (high LE8 score vs. low LE8 score: HR = 0.300, 95% CI 0.270-0.330, p < 0.001; median LE8 score vs. low LE8 score: HR = 0.531, 95% CI 0.487-0.580, p < 0.001). This strong LE8-CKD association remained robust in extensive subgroup assessments and sensitivity analysis. Additionally, these noteworthy associations between LE8 scores and CKD remained unaffected by genetic predispositions to CKD. CONCLUSIONS: An elevated degree of CVH, as delineated by the discerning metric LE8, exhibited a pronounced and statistically significant correlation with a marked reduction in the likelihood of CKD occurrence.

Newly identified lineages of porcine hemagglutinating encephalomyelitis virus exhibit respiratory phenotype.

Swine pathogens have a long history of zoonotic transmission to humans, occasionally leading to sustained outbreaks or pandemics. Through a retrospective epidemiological study of swine populations in China, we describe novel lineages of porcine hemagglutinating encephalomyelitis virus (PHEV) complex coronaviruses (CoVs) that cause exclusively respiratory symptoms with no signs of the neurological symptoms typically associated with classical PHEV infection. Through large-scale epidemiological surveillance, we show that these novel lineages have circulated in at least eight provinces in southeastern China. Phylogenetic and recombination analyses of twenty-four genomes identified two major viral lineages causing respiratory symptoms with extensive recombination within them, between them, and between classical PHEV and the novel respiratory variant PHEV (rvPHEV) lineages. Divergence times among the sampled lineages in the PHEV virus complex date back to 1886-1958 (mean estimate 1928), with the two major rvPHEV lineages separating approximately 20 years later. Many rvPHEV viruses show amino acid substitutions at the carbohydrate-binding site of hemagglutinin esterase (HE) and/or have lost the cysteine required for HE dimerization. This resembles the early adaptation of human CoVs, where HE lost its hemagglutination ability to adapt to growth in the human respiratory tract. Our study represents the first report of the evolutionary history of rvPHEV circulating in swine and highlights the importance of characterizing CoV diversity and recombination in swine to identify pathogens with outbreak potential that could threaten swine farming.

Comparative Genomic Analysis of Hypervirulence Carbapenem-Resistant Klebsiella pneumoniae from Inpatients with Infection and Gut Colonization, China.

Background: The emergence and spread of hypervirulent carbapenem-resistant Klebsiella pneumoniae (hv-CRKP) is a potential epidemiological threat that needs to be monitored. However, the transmission and pathogenic characteristics of hv-CRKP in China remain unclear. We investigated the epidemiological characteristics of gut colonized hv-CRKP in a hospital in Guangdong Province, China. Methods: A total of 46 gut colonized hv-CRKP isolates were collected from Sun Yat-Sen Memorial Hospital (Guangzhou, China) from August 31st to December 31st, 2021. Minimum inhibitory concentrations (MICs) were obtained for 15 antibiotics for 46 hv-CRKP isolates. BALB/C mice infection model and mucoviscosity assay was used to evaluate the virulence of the isolates. The characteristics of genome, phylogenetic relationship and the structure of the plasmid of 46 gut colonized hv-CRKP isolates were compared with pathogenic isolates from GeneBank based on whole-genome data. Results: The hv-CRKP isolation rate of all gut colonized carbapenem-resistant Klebsiella pneumoniae was 17% (46/270), and the intestinal colonization rate of hv-CRKP was irrelevant to the sex, age, department of hospitalization, and history of antibiotic use of the host. The gut colonized hv-CRKP showed pandrug resistance and hypervirulence. The gut colonized hv-CRKP and pathogenic hv-CRKP prevalent in China were mainly ST11 hv-CRKP and had two major epidemic clades. The similarities in genomic characteristics between gut colonized hv-CRKP and pathogenic hv-CRKP were consistent. The gut colonized hv-CRKP carried an incomplete structure pK2044 virulence plasmid from hypervirulent K. pneumoniae NTUH-K2044 by analyzing the virulence plasmid structure. Conclusion: Our results suggest that the gut colonized ST11 hv-CRKP may serve as a reservoir for the clinical pathogenic ST11 HV-CRKP. It is necessary to further strengthen the monitoring of gut colonized hv-CRKP and research the potential mechanism of infection caused by gut colonized hv-CRKP.

Forkhead box protein K1­regulated neurexophilin 4 promotes proliferation, metastasis and glycolysis in colorectal cancer.

Colorectal cancer (CRC) is a common malignant tumor. At present, the in-depth study of the formation, development and treatment of CRC at the molecular and gene levels is a research hot spot. Neurexophilin 4 (NXPH4) expression has been revealed to be abnormally elevated in several types of cancer, but its expression in CRC has not yet been reported. First, relevant databases were used to predict the expression of NXPH4 in CRC and its association with the survival rate of patients with CRC. Subsequently, the expression of NXPH4 in CRC cells was verified through cell experiments. Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, wound healing assay, Transwell assay, western blotting and the kits were used to detect the effects of NXPH4 knockdown in CRC cells on cell proliferation, invasion, migration and glycolysis. The association between NXPH4 and forkhead box protein K1 (FOXK1) was predicted using the JASPAR database, and verified through luciferase reporter gene and chromatin immunoprecipitation experiments. The NXPH4 regulation mechanism was also discussed. NXPH4 was revealed to be highly expressed in CRC. NXPH4 knockdown in CRC cells could significantly inhibit cell proliferation and induce apoptosis. NXPH4 knockdown inhibited cell invasion, migration and glycolysis. The aforementioned process could be reversed by further FOXK1 overexpression in CRC cells. In conclusion, FOXK1-regulated NXPH4 promotes proliferation, metastasis and glycolysis in CRC.

Effectiveness of personalized smoking cessation intervention based on ecological momentary assessment for smokers who prefer unaided quitting: protocol for a randomized controlled trial.

Introduction: Ecological momentary assessment (EMA)-based smoking cessation intervention may help personalize intervention for smokers who prefer to quit smoking unaided. This study aims to evaluate the effectiveness of EMA-based phone counseling and instant messaging for smoking cessation. Methods/design: This is a two-arm, accessor-blinded, simple individual randomized controlled trial (allocation ratio 1:1). Participants will be recruited from community sites and online platforms in Hong Kong. Interventions will be delivered via a phone call and instant messaging. Current adult smokers who (1) self-report no intention to use smoking cessation services and medication in the coming month and (2) have not used smoking cessation services or nicotine replacement therapy in the past 7 days will be recruited. Recruited participants will be randomized to intervention or control groups via an online randomizer. All participants will be required to complete EMAs (five times per day for 7 consecutive days). The intervention group (n = 220) will receive a nurse-led brief phone counseling immediately after the 1-week EMAs and 10-week EMA-based advice via instant messaging applications (e.g., WhatsApp, WeChat). The 10-week EMA-based advice covers a summary of the 1-week EMAs, and tailored cessation support focused on personalized smoking triggers. The control group (n = 220) will not receive any intervention during the same period. The primary outcomes are participants' progression toward smoking cessation assessed by the Incremental Behavior Change toward Smoking Cessation (IBC-S) and biochemically validated abstinence at the 3-month follow-up. Secondary outcomes include self-reported and biochemically validated tobacco abstinence at the 6-month follow-up. Discussion: The findings will provide evidence that the EMA-based tailored smoking cessation intervention can be adapted as a new health promotion strategy for current smokers who are unwilling to use smoking cessation aids. Clinical trial registration: https://classic.clinicaltrials.gov/ct2/show/NCT05212220, identifier: NCT05212220.

Antibiotic-Polymer Self-Assembled Nanocomplex to Reverse Phenotypic Resistance of Bacteria toward Last-Resort Antibiotic Colistin.

Colistin is the last-resort antibiotic to treat multidrug-resistant (MDR) Gram-negative bacterial infections that are untreatable by other clinically available antibiotics. However, the recently merged plasmid-borne gene mobilized colistin resistance (mcr) leads to modification of the colistin target (i.e., bacterial membrane), greatly compromising the therapy outcome of colistin. To address this unmet clinical need, a nanocomplex (CMS-pEt_20 NP) of anionic prodrug colistin methanesulfonate (CMS) and guanidinium-functionalized cationic polymer pEt_20 is developed through facile self-assembly for co-delivering an antibiotic and antimicrobial polymer with membrane affinity to reverse colistin resistance. The CMS-pEt_20 NP formation enables reversal of colistin resistance and complete killing of clinically isolated mcr-positive colistin-resistant bacteria including MDR E. coli and K. pneumoniae, while monotreatment of polymer or antibiotic at equivalent doses exhibits no antibacterial activity. Mechanistic studies reveal that the CMS-pEt_20 NP enhanced the affinity of delivered CMS to the modified membrane of colistin-resistant bacteria, reviving the membrane lytic property of colistin. The increased membrane permeability caused by colistin in turn promotes an influx of pEt_20 to generate intracellular ROS stress, resulting in elimination of colistin-resistant bacteria. More importantly, a colistin-resistant mouse peritonitis-sepsis infection model demonstrates the excellent therapeutic efficacy of CMS-pEt_20 NP with 100% survival of the infected mouse. In addition, the nanocomplex is proven not toxic both in vitro and in vivo. Taken together, the self-assembled antibiotic-polymer nanocomplex with two complementary antibacterial mechanisms successfully reverses the colistin resistance phenotype in bacteria, and it can be a potential strategy to treat untreatable colistin-resistant MDR bacterial infections.

Mutation and codon bias analysis of the spike protein of Omicron, the recent variant of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is a heavily mutated virus and designated as a variant of concern. To investigate the codon usage pattern of this new variant, we performed mutation and codon bias analysis for Omicron as well as for its sub-lineages BA.1 and BA.2 and compared them with the original SARS-CoV-2 and the Delta variant sequences obtained in this study. Our results indicate that the sub-lineage BA.1 and BA.2 have up to 23 sites of difference on the spike protein, which have minimal impact on function. The Omicron variant and its sub-lineages have similar codon usage patterns and A/U ending codons appear to be preferred over G/C ending codons. The Omicron has a lower degree of codon usage bias in spite of evidence that natural selection, mutation pressure and dinucleotide abundance shape the codon usage bias of Omicron, with natural selection being more significant on BA.2 than the other sub-lineages of Omicron. The codon usage pattern of Omicron variant that we explored provides valid information for a clearer understanding of Omicron and its sub-lineages, which could find application in vaccine development and optimization.

Tendon-inspired hybrid hydrogel based on polyvinyl alcohol and gallic acid-lysozyme for promoting wound closure and healing.

Noninvasive wound closure remains a challenge in the field of wound healing. In this study, we report the development of a cross-linked P-GL hydrogel constructed from polyvinyl alcohol (PVA) and GL (a hydrogel consisting of gallic acid and lysozyme) that effectively promotes wound closure and healing. The P-GL hydrogel exhibited a unique lamellar and tendon-like fibrous network structure, providing good thermo-sensitivity and tissue adhesiveness up to 60 MPa, as well as retaining autonomous self-healing and acid resistance capacities. In addition, the P-GL hydrogel exhibited sustained release characteristics lasting >100 h, excellent biocompatibility both in vitro and in vivo, as well as good antibacterial activity and mechanical properties. The in vivo full-thickness skin wounds model revealed the positive wound closure and healing therapeutic effects of the P-GL hydrogels were confirmed, showing a promising potential as a noninvasive wound closure and healing bio-adhesive hydrogel.

Plasma osteoprotegerin predicts adverse cardiovascular events in stable coronary artery disease: the PEACE trial.

Background: Osteoprotegerin (OPG) is a secretory glycoprotein and participates in the progression of atherosclerotic lesions. We aim to explore the relationship between OPG and the prognosis of coronary artery disease (CAD). Methods: Plasma OPG concentrations were measured in 3,766 patients with stable CAD enrolled in the PEACE trial. The PEACE trial (NCT00000558) group followed up the patients and examined their future clinical outcomes. Results: In summary, 208 (5.5%) primary outcomes occurred, 295 patients (7.8%) died from all-cause death, 128 (3.4%) died from cardiovascular causes, and 94 (2.5%) experienced heart failure during a median follow-up of 1,892 days. In addition, we found that higher plasma levels of OPG were associated with a higher incidence of all-cause death, cardiovascular death, and heart failure, even after adjusting clinical cofounders. Conclusion: It was demonstrated that elevated plasma OPG levels were associated with an increased incidence of all-cause death, cardiovascular death, and heart failure in patients with stable CAD. Systematic Review Registration: https://clinicaltrials.gov/ct2/show/NCT00000558?term=NCT00000558&draw=2&rank=1, identifier: NCT00000558.